Editors' ChoicePhysiology

Muscling Out Depression

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Science Signaling  07 Oct 2014:
Vol. 7, Issue 346, pp. ec274
DOI: 10.1126/scisignal.2005996

Depression is a heterogeneous mood disorder. Associated features include increases in the neurotransmitter glutamate and the metabolite kynurenine, both of which can be caused by stress and lead to neuron damage. Physical exercise is therapeutic for many people suffering from depression or stress. Skeletal muscle activity during endurance-type exercise activates peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1-α1 (PGC1-α1). Agudelo et al. investigated the molecular mechanism underlying the antidepressive effects of exercise. Compared with wild-type mice or an unstressed cohort, mice with skeletal muscle-specific overexpression of PGC1-α1 (mck-PGC1-α1 mice) exposed to chronic mild stress were less likely to show depression-like behavior and abnormal abundance of synaptic proteins. Less of the stress-related corticotrophin-releasing hormone was produced in the hypothalamus of mck-PGC1-α1 mice than in wild-type mice exposed to chronic mild stress, and only in stressed wild-type mice did the hypothalamus have increased amounts of proinflammatory cytokines and markers of macrophage and microglia activity.

Tissue microarray and serum analysis of unstressed or stressed wild-type or mck-PGC1-α1 mice showed that only stressed wild-type mice had increased abundance of rate-limiting enzymes of the kynurenine pathway in skeletal muscle, kynurenine in plasma, and kynurenine metabolites in the brain. In contrast, only stressed mck-PGC1-α1 mice had increased abundance of kynurenine acetyltransferase (KAT) in skeletal muscle and plasma. KAT catalyzes the conversion of kynurenine to kynurenic acid, which unlike kynurenine, cannot transverse the blood-brain barrier. Myotubes overexpressing PGC1-α1 had increased abundance of KAT transcripts. The genomic regions around the KAT1, KAT3, and KAT4 loci are enriched in binding elements for the PGC1-α1 transcriptional partners PPAR-α and PPAR-δ; chromatin immunoprecipitation showed increased binding of PPAR-α/δ and PGC1-α1 to regions upstream of the KAT transcription start sites in mck-PGC1-α1 mice. Compared to wild-type mice or an unstressed cohort, respectively, the abundance of PPAR-α and PPAR-δ was increased in mck-PGC1-α1 mice and further increased in mck-PGC1-α1 mice exposed to chronic mild stress. Agonists of PPAR-α or PPAR-δ increased the abundance of KATs 1 and 3 in myotubes in a PGC1-α1-dependent manner. Compared with inactive mice, wild-type mice that underwent a free wheel running exercise program for 8 weeks had increased expression of KATs in skeletal muscle and increased abundance of plasma kynurenic acid, both characteristics also present in nonexercised mck-PGC1-α1 mice. Biopsies from the thigh muscle in humans before and after a 3-week exercise program showed that exercise induced the expression of the genes encoding PPAR-α and δ, PGC1-α1, and KATs 1-4. The findings reveal a mechanism by which exercise helps animals cope with stress.

L. Z. Agudelo, T. Femenía, F. Orhan, M. Porsmyr-Palmertz, M. Goiny, V. Martinez-Redondo, J. C. Correia, M. Izadi, M. Bhat, I. Schuppe-Koistinen, A. T. Pettersson, D. M. S. Ferreira, A. Krook, R. Barres, J. R. Zierath, S. Erhardt, M. Lindskog, J. L. Ruas, Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159, 33–45 (2014). [PubMed]